New cholesterol drug shows promise

“Heart attack risk could be cut by new cholesterol lowering drug,” The Guardian reports.

This headline – and others like it – stretch the findings from an early safety trial of ALN-PCS, a new drug that targets LDL (or ‘bad’) cholesterol.

Such trials are not designed to see whether a drug is effective, and in this case, the trial had too few people involved to be able to tell.

ALN-PCS belongs to a class of molecules known as small interfering RNAs or siRNAs. The drug is designed to block the effects of a protein, called PCSK9, that is associated with cholesterol levels.

The trial included 32 healthy people and found that a single dose of the new drug was safe and well tolerated. Further trials are planned to assess the long-term safety and effectiveness of the drug in people with high cholesterol who need lipid-lowering medications such as statins.

As this was just a phase I trial the drug was not compared to other cholesterol-lowering drugs, and information on long-term outcomes, such as reduced risk of heart attacks, was not assessed. Also, the drug was tested in healthy volunteers and not among individuals with very high cholesterol levels who would normally need such treatment.

Further research, in the form of a phase II clinical trial is now required.

Where did the story come from?

The study was carried out by researchers from Alnylam Pharmaceuticals, the University of Texas South Western in the US, Guy’s Hospital in London, and Covance Clinical Research Unit, Leeds. The trial was funded by Alnylam Pharmaceuticals.

A number of the researchers involved in the study are employees of, and/or stock owners in Alnylam Pharmaceuticals, which represents a potential conflict of interest (which was declared in the study).

The study was published in the peer-reviewed medical journal, The Lancet.

Media coverage of the study was mixed, with most headlines focusing on the cholesterol lowering effects of the drug. This was despite the fact that this was not the main aim of the study, and that it was not large enough to detect such changes. The Daily Telegraph did go on to report that, “larger studies would now be needed to check long-term safety and tolerability of the drug on patients who take statins as well as those who cannot take the drugs”.

What kind of research was this?

This was a phase I clinical trial (a randomised controlled trial) that assessed the safety and tolerability of a newly developed cholesterol lowering drug called ALN-PCS.

ALN-PCS is a small interfering RNA (siRNA) molecule, which prevents the production of a protein called PCSK9. PCSK9 has been shown to bind to other proteins called LDL receptors, which are responsible for clearing ‘bad’ LDL cholesterol from the blood. When these receptors are blocked by PCSK9, LDL cholesterol builds up in the blood. There is substantial evidence that high LDL cholesterol levels increase the risk of coronary heart disease.

ALN-PCS works by interrupting the production of PCKS9. The process by which such siRNA molecules interrupt gene expression is called RNA interference (RNAi).

Based on previous research in animals, researchers expected that when participants received ALN-PCS, the levels of PCSK9 in their blood would drop, and a corresponding reduction in LDL cholesterol would be seen.

What did the research involve?

The researchers recruited 32 healthy volunteers with mild to moderately elevated LDL cholesterol. They were randomly assigned to receive either a placebo infusion of a salt solution or a single infusion of the drug, called ALN-PCS, into a vein.

The night and morning before the infusion, volunteers were given a pre-treatment including paracetamol, a corticosteroid and an antihistamine. This was in order to reduce the chances of an adverse reaction to the infusion of the drug.

As a phase I trial, the main aim of the study was to determine whether the drug was safe, and which doses were tolerable by people. As such, six different doses of ALN-PCS were tested, and the primary outcome of the study was the frequency and severity of adverse events (side effects).

As a secondary outcome, the researchers checked for changes in PCSK9 and LDL cholesterol levels in the blood, measured at the beginning of the study and seven days after the drug infusion.

What were the basic results?

Of the 32 healthy participants, 24 were randomly assigned to receive the drug (ALN-PCS) and eight to receive placebo.

Treatment with ALN-PCS was found to be both safe and well tolerated at all doses.

No one receiving the drug experienced any drug-related serious side effects. One patient receiving a low dose was diagnosed with a serious condition on the third day of the study. However, this was determined to be unrelated to the drug being trialled.

Overall, similar proportions of patients receiving ALN-PCS and placebo experienced mild to moderate side effects (79% in the treatment group and 88% in the placebo group).

The researchers also found that the single dose of ALN-PCS was found to significantly reduce concentrations of PCSK9 in the blood, with greater reductions seen at higher drug doses. This was associated with a reduction in LDL cholesterol levels, with higher drug doses causing greater and longer reductions in cholesterol concentrations. The highest drug dose resulted in an average reduction of 40%, compared to placebo.

How did the researchers interpret the results?

The researchers concluded that treatment with the RNAi drug ALN-PCS was safe and well tolerated, and that “future trials are needed to fully assess the benefit and long-term safety of ALN-PCS in various patient populations” including patients who are receiving statins as well as patients who cannot tolerate statins.


Media headlines reporting on this phase I trial concentrated on the secondary outcome (that ALN-PCS reduced LDL cholesterol levels). However, these results will need to be confirmed during phase II and phase III clinical trials, which will involve more participants who would normally receive cholesterol-lowering treatment.

While it is tempting to focus on the results of the cholesterol levels, phase I clinical trials are designed to test the safety of a new drug to make sure it is safe enough to test further. They also aim to determine what the highest tolerable dose is, so the appropriate one can be used in later studies. For those reasons, they involve testing the drug in a small group of healthy individuals.

The researchers note (although no media outlets seemed to report on this aspect of the study) that the study was too small to detect statistically significant changes in PCSK9 or LDL cholesterol levels compared with placebo group.

The results of this study will be used to design further phase II and phase III trials, which will further characterise the safety profile of the drug and determine its effectiveness at reducing LDL cholesterol among people who need cholesterol-lowering medications. Only then can we determine whether the drug offers an effective option for managing high LDL cholesterol.

While perhaps less immediately interesting from the general public’s perspective, one of the more exciting aspects of this research is that it is the first time an RNA interference drug has been shown – in humans – to lower a protein that is made in the liver. It is also the first time such a drug has shown a measurable health benefit, even though this was not the primary outcome of the study.

The process of RNA interference is a relatively new discovery (first described in 1998), and substantial research efforts have been directed towards the development of siRNA treatments for human disease. This field of research has hit several hurdles, so this study showing potential clinical benefit from siRNA treatment is exciting news for scientists.

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